The invention relates to new compounds of formula I, 
wherein the groups Ar, R1, R2, R3 and R4 have the meanings given in the claims and specification, processes for preparing them as well as their use as pharmaceutical compositions, and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
The compounds of formula I are partly covered by the broad general formula of International Patent Application WO97/32865. However, this does not disclose any compounds in which the piperidyl group in the 4 position is substituted by a 3-hydroxypropylamino, cycloalkylmethylamino or 1,3-dihydroxyprop-2-ylamino group. The compounds described in this international patent application are highly effective neurokinin antagonists with a broad spectrum of activity.
The problem of the present invention is to provide new neurokinin antagonists with an extended duration of activity. This problem is now solved according to the invention by the preparation of the new compounds of formula I.
Surprisingly it has been found that the duration of activity of NK1 receptor antagonists can be dramatically extended if an amino group of formula A 
wherein
R1 denotes 3-hydroxypropyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl, and
R2 denotes hydrogen, C1-C6-Alkyl, xcfx89-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl,
is inserted into these compounds.
The invention therefore relates to the use of an NK1 receptor antagonist which contains an amino group of formula A, 
wherein
R1 denotes 3-hydroxypropyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl, and
R2 denotes hydrogen, C1-C6-alkyl, xcfx89-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl,
or the pharmaceutically acceptable salts thereof,
for preparing a medicament with an extended period of activity for the treatment and prevention of neurokinin-mediated illnesses.
The invention further relates to new compounds of formula I 
or the pharmaceutically acceptable salts thereof,
wherein
R1 denotes 3-hydroxypropyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl,
R2 denotes hydrogen, C1-C6-alkyl, xcfx89-hydroxy-C2-C4-alkyl, 1,3-dihydroxyprop-2-yl or C3-C6-cycloalkylmethyl,
Ar denotes unsubstituted phenyl or phenyl which is 1- to 5-substituted by halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy or xe2x80x94OCH2Oxe2x80x94;
R3 denotes phenyl-C1-C4-alkyl, wherein the phenyl group may be substituted by 1 to 3 substituents, wherein the substituents independently of one another are selected from among halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy; and
R4 denotes hydrogen, C1-C4-alkyl, C3-C8-cycloalkyl, CH2COOH, xe2x80x94CH2C(O)NH2, xe2x80x94OH or phenyl-C1-C4-alkyl.
In the foregoing and in what is to follow, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d as used with reference to the groups R1, R2, R3, R4 or the substituents of Ar denote straight-chain or branched, saturated hydrocarbon groups with up to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy or i-propoxy.
In the foregoing and in what is to follow, the term xe2x80x9ccycloalkylxe2x80x9d as used with reference to the groups R1, R2 and R4 denotes a cycloalkyl group with up to 8 carbon atoms, preferably 3 to 6 carbon atoms, particularly cyclopropyl, cyclopentyl or cyclohexyl.
In the foregoing and in what is to follow, the terms xe2x80x9cfluoroalkylxe2x80x9d and xe2x80x9cfluoroalkoxyxe2x80x9d as used with reference to the group R3 or the substituents of Ar denote straight-chain or branched, fluorine-substituted hydrocarbon groups with up to 4 carbon atoms and up to 9 fluorine atoms, preferably 1 or 2 carbon atoms and up to 5 fluorine atoms, particularly trifluoroethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 2-fluoroethoxy.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses and additionally have a long-lasting effect.
Compounds of general formula I may have acid groups, mainly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be in the form of internal salts, salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine etc.
The compounds according to the invention may occur as racemates, or they may be obtained as pure enantiomers, i.e. in the (R)- or (S)-form. Compounds which occur as racemates or as the (S)-form are preferred.
The compounds according to the invention are valuable neurokinin (tachykinin)-antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses:
Treatment or prevention of inflammatory and allergic complaints of the airways, such as asthma, chronic bronchitis, hyperreactive airways, emphysema, rhinitis, COPD, pulmonary hypertension, cystic fibrosis, coughs;
of the eyes, such as conjunctivitis and iritis;
of the skin, such as dermatitis in contact eczema, neurodermatitis, pruritus, urticaria, psoriasis, sunburn, burns, insect bites, rosacea, itching, sensitive or hypersensitive skin, of the gastro-intestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn""s disease, inflammatory bowel disease, irritable colon, Hirschsprung""s disease, motility problems;
of the joints or bones, such as rheumatoid arthritis, reactive arthritis, arthrosis, osteoporosis and Reiter""s syndrome;
of the bladder, such as irritable bladder, incontinence, urinary urgency, urethritis, colic and cystitis, as well as restless leg syndrome.
Also for the treatment of diseases of the central nervous system such as dementia, Alzheimer""s disease, schizophrenia, psychoses, anxiety states, alcohol or drug dependency, sexual dysfunctions, eating disorders, depression, headaches (e.g. migraine or tension headaches), epilepsy; parkinson""s disease, stroke, treatment of Herpes zoster as well as postherpetic pain, tumours, collagenoses, a dysfunction of the deferent urinary tracts, haemorrhoids, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion, and painful conditions of all kinds.
Because of their long-lasting activity the compounds according to the invention are particularly suitable for the treatment and/or prevention of COPD or depression accompanied by anxiety states.
The invention therefore also relates to the use of the compounds of formula I as curative agents and pharmaceutical preparations which contain these compounds. They are preferably used on humans. The compounds according to the invention may be given intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, optionally assisted by iontophoresis or enhancers known from the literature, and by oral route.
For parenteral administration the compounds of formula I or their physiologically acceptable salts may be put into solution, suspension or emulsion, possibly with substances conventionally used for this purpose such as solubilisers, emulsifiers or other adjuvants. Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents.
In addition, the compounds may be administered by the use of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
Compounds of formula I, wherein R4 denotes C1-C4-alkyl, particularly methyl, are preferred.
Also preferred are compounds of formula I wherein Ar is unsubstituted phenyl or 2,3-methylenedioxyphenyl, particularly unsubstituted phenyl.
Preferred compounds of formula I are those wherein R3 denotes 2-phenylethyl, wherein the phenyl group may be substituted by 1 to 3 substituents, wherein the substituents are selected independently of one another from among halogen, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, particularly wherein R3 is 2-(3,5-bis-trifluoromethylphenyl)-ethyl.
Particularly preferred compounds of formula I are those wherein the group xe2x80x94NR3R4 is 
In a preferred aspect the invention relates to compounds of formula I, wherein
R1 denotes a cyclopropylmethyl group, and
R2 denotes a hydrogen atom, a C1-C3-alkyl group or a 3-hydroxypropyl group.
In another preferred aspect the invention relates to compounds of formula I, wherein R1 denotes a 3-hydroxypropyl or 1,3-dihydroxyprop-2-yl group, and R2 denotes a hydrogen atom, a C1-C3-alkyl group or a 2-hydroxyethyl group.
Particularly preferred are NK1 receptor antagonists which contain an amino group selected from among formulae A-1 to A-5
The following compounds are particularly preferred: 
The compounds may be prepared in a manner known per se. Advantageous methods are illustrated and described in the following diagrams.
The compounds of general formula I may be prepared by reacting an amide of formula II 
wherein X denotes a suitable leaving group, preferably halogen, alkylsulphonyloxy, particularly methylsulphonyloxy, or arylsulphonyloxy, particularly p-tolylsulphonyloxy,
with a piperidine of general formula III 
in an inert solvent in the presence of a base.
This process is illustrated by means of the following Diagram 1 for compounds wherein Ar is phenyl, R3 is bis-(trifluoromethyl)-phenylethyl and R4 is methyl. However, the process can be used analogously for all compounds of formula I.
First of all, 4-oxo-piperidine protected in the 1 position is reacted with an amine of formula R1R2NH, wherein R1 and R2 have the meanings given for formula I. In the next step the double bond of the imine or enamine group is reduced with a complex reducing agent, preferably an alkali metal alanate or alkali metal boranate, particularly sodium boranate or sodium triacetoxyborohydride. Alternatively the compounds (d) may be obtained starting from the compounds (c) by a second reductive amination by reacting with correspondingly substituted ketones or aldehydes under reductive conditions; in particular a methyl group can be introduced by reducing alkylation with formaldehyde and formic acid. 
The piperidine derivative with an unsubstituted piperidine-N is then obtained by cleaving the protecting group with a cleaving reagent, preferably by hydrolysis of a Boc group or hydrogenation of a benzyl group.
The reactant for this piperazine derivative is obtained as shown in Diagram 1, on the right. (R)-Mandelic acid is reacted with methanesulphonic acid halide to obtain (R)-2-methanesulphonyloxy)-acetic acid. This is then reacted with a coupling reagent and the correspondingly substituted phenethylamine to obtain the corresponding amide, or it is converted into the corresponding acid halide (e.g. with SOCl2/SO2Cl2) and then converted with the suitably substituted phenethylamine into the corresponding amide. In the last step the amide thus obtained is reacted with the piperidine derivative described above, while during the substitution of methanesulphonate Cxe2x80x94N-linking takes place with simultaneous reversal of the chiral centre. The reaction is carried out in an inert solvent, preferably a polar aprotic solvent such as, for example, DMF, dimethyl acetamide, acetone, ethylmethylketone or acetonitrile in the presence of a base, preferably a tertiary amine, such as, for example, TEA or N-methylmorpholine, or an alkali metal carbonate or an alkali metal hydrogen carbonate, such as, for example, potassium carbonate at temperatures between 20xc2x0 C. and 120xc2x0 C. The reaction time is between 0.5 h and 48 h.